CD33, a member of the sialic acid binding, immunoglobulin-like lectin family, is a 67-kDa glycosylated transmembrane protein. It is expressed on most myeloid and monocytic leukemia cells in addition to committed myelomonocytic and erythroid progenitor cells. It is not seen on the earliest pluripotent stem cells, mature granulocytes, lymphoid cells, or nonhematopoietic cells. See Sabbath et al., J. Clin. Invest. 75:756-56 (1985) and Andrews et al., Blood 68:1030-5 (1986). CD33 contains two tyrosine residues on its cytoplasmic tail, each of which is followed by hydrophobic residues similar to the immunoreceptor tyrosine-based inhibitory motif (ITIM) seen in many inhibitory receptors.
Monoclonal antibody (mAb)-based therapy has become an important treatment modality for cancer. Leukemia is well suited to this approach because of the accessibility of malignant cells in the blood, bone marrow, spleen, and lymph nodes and the well-defined immunophenotypes of the various lineages and stages of hematopoietic differentiation that permit identification of antigenic targets. Most studies for acute myeloid leukemia (AML) have focused on CD33. Responses with the unconjugated anti-CD33 mAb lintuzumab have had modest single agent and activity against AML and failed to improve patient outcomes in two randomized trials when combined with conventional chemotherapy. The immunoconjugate gemtuzumab ozogamicin (GO; Mylotarg), an anti-CD33 monoclonal antibody conjugated to the antitumor antibiotic calicheamicin, improved survival in a subset of AML patients when combined with standard chemotherapy, but safety concerns led to marketing withdrawal in the US. Additionally, three phase I studies of an anti-CD33-maytansine conjugate (AVE9633; huMy9-6-DM4) in AML patients. The maximum tolerated dose (MTD) was determined only in one of the phase I studies (administration schedule day 1/8) as the other two studies were discontinued before reaching the MTD since no signs of activity were apparent at doses much higher than the saturating dose. The activity of AVE9633 in the phase I administration schedule day 1/8 was modest. Lapusan et al., Invest. New Drugs 30:1121-1131 (2012).
There is a need in the art for safe and effective agents that target CD33 for the diagnosis and treatment of CD33-associated conditions, such as cancer. The invention fulfills that need and provides other benefits.